Method for producing 2-alkyl-3-chlorophenols

ABSTRACT

The invention relates to a novel process for preparing 2-alkyl-3-chlorophenols.

[0001] The invention relates to a novel process for preparing2-alkyl-3-chlorophenols.

[0002] 2-Alkyl-3-chlorophenols are intermediates which can be used, forexample, for preparing crop protection agents (cf. WO 98/21189).

[0003] It is already known that 3-chloro-2-methylphenol can be obtainedby reacting 2-chlorotoluene with sodium methoxide inhexamethylphosphoramide (HMPA) as solvent and treatment of the reactionsolution with sodium isopropylthiolate. One disadvantage of this processis the use of HMPA as solvent, since it is highly carcinogenic. Also,the sodium isopropylthiolate used and the isopropylthiol released duringthe work-up are very odorous. For these reasons, this process is notapplicable on the industrial scale.

[0004] In another process (cf. Justus Liebigs Ann. Chem., 350, 1906,112), the preparation of 3-chloro-2-methylphenol takes place startingfrom 2-amino-6-chlorotoluene. Diazotization using nitrous acid andsubsequent hydrolysis in a boiling mixture of water and sulphuric acidgives 3-chloro-2-methylphenol.

[0005] A significant disadvantage of this process is that the startingmaterial cannot be prepared in isomerically pure form. High levels ofby-products are isolated, which results in low yields. Also, thediazonium salt formed is of limited solubility so that the process mustbe operated in high dilution, which makes the preparation of3-chloro-2-methylphenol on the industrial scale more difficult. Afurther disadvantage is that a steam distillation must be carried out,whose operation, particularly on the industrial scale, is costly andinconvenient.

[0006] It has been found that 2-alkyl-3-chlorophenols of the generalformula (I)

[0007] where

[0008] R is C₁-C₆-alkyl, are obtained when alkyldichlorobenzenederivatives of the general formula (II)

[0009] where

[0010] R has the above meanings, are reacted

[0011] a1) with a base in a high-boiling organic diluent of the generalformula (III)

R¹—OH   (III),

[0012] where

[0013] R¹ is

[0014] R²—O—(CH₂)₂—O—(CH₂)₂—,

[0015] R²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—,

[0016] R²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—O—(CH₂)₂— or

[0017] —C₆ to C₁₀-alkyl,

[0018] where R² is hydrogen, methyl or ethyl, optionally in the presenceof a catalyst, and the water released by the reaction is continuouslyremoved,

[0019] or are reacted

[0020] a2) with a base in a high-boiling organic diluent of the generalformula (III)

R¹—OH   (III),

[0021] where

[0022] R¹ has the above meanings, optionally in the presence of acatalyst, and any water released during the reaction is continuouslyremoved, and the resulting compounds of the formula (IV)

[0023] where

[0024] R and R¹ have the above meanings, are treated with relativelyhighly concentrated acid,

[0025] or are reacted

[0026] b1) with a base in a primary alcohol having 1 to 3 carbon atomsused as a diluent under pressure,

[0027] or are reacted

[0028] b2) with a base in a primary alcohol having 1 to 3 carbon atomsused as a diluent under pressure, and the resulting compounds of theformula (IV)

[0029] where

[0030] R and R¹ have the above meanings, are treated with relativelyhighly concentrated acid.

[0031] After operation of the process variants a1) and b1), the reactionmixture is acidified with a dilute acid.

[0032] In the compounds of the formula (II), R is in particular methyl,ethyl, n- or i-propyl.

[0033] In the compounds of the formula (II), R is more preferablymethyl.

[0034] In the compounds of the formula (III), R¹ is more preferablyHO—(CH₂)₂—O—(CH₂)₂—.

[0035] The radical definitions listed above or given as preferredmeanings apply both to starting compounds of the formulae (II) and (III)and correspondingly to the final products of the formula (I) and theintermediates of the formula (IV).

[0036] The specific radical definitions given for the combinations orcombinations of radicals in question are, independently of thecombination of the radicals given, alternatively arbitrarily replaced byradical definitions of other preferred meanings.

[0037] It is particularly surprising to note that, in the process of theinvention, 2-alkyl-3-chlorophenols are obtained in high yields and highpurity, since, for other comparable reactions, more drastic reactionconditions, such as hydrolysis to give phenols in a boiling mixture ofwater and sulphuric acid, are required.

[0038] The process of the invention has a whole series of advantages.For instance, 2-alkyl-3-chlorophenols can be prepared usingnon-carcinogenic solvents and without the reaction having to be carriedout at high dilution. Therefore, the novel process is particularlysuitable for industrial scale applications.

[0039] The compounds of the general formula (IVa) are hitherto unknownand as novel chemical compounds also form part of the subject-matter ofthe present invention

[0040] In the compounds of the formula (IVa),

[0041] R¹

[0042] is R²—O—(CH₂)₂—O—(CH₂)₂—,

[0043] R²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—, or

[0044] R²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—O—(CH₂)₂—,

[0045] where R² is hydrogen, methyl or ethyl.

[0046] In the compounds of the formula (IVa), R¹ is more preferablyHO—(CH₂)₂—O—(CH₂)₂—.

[0047] The alkyldichlorobenzene derivatives of the general formula (II)and all other starting compounds are currently commercially availableproducts or can be prepared from these by simple processes.

[0048] Examples of preferred diluents of the general formula (m) foroperating the process variants a1) and a2) include diethylene glycol,triethylene glycol, tetraethylene glycol or higher-boiling primaryalcohols. The process variants a1) and a2) are preferably carried outusing diethylene glycol.

[0049] The process variants a1) and a2) of the invention are operated inthe presence of a suitable acid acceptor. Examples of preferred acidacceptors include alkaline earth metal or alkali metal hydroxides,alkoxides or carbonates, such as sodium methoxide, potassiumtert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonateand potassium carbonate. The process variants a1) and a2) are preferablycarried out using sodium hydroxide or, in particular, potassiumhydroxide.

[0050] The process variants a1) and a2) of the invention are optionallycarried out in the presence of a suitable catalyst. Preferred catalystsinclude tertiary amines, such as trimethylamine, triethylamine,tributylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, pyridine,picoline, 2-methyl-5-ethylpyridine, N-methylpiperidine,N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).

[0051] The process variant a1) of the invention is operated using diluteacids, in particular mineral acids, preferable examples of which includesulphuric acid, phosphoric acid, and in particular hydrochloric acid.

[0052] The process variant a2) of the invention is preferably carriedout using more highly concentrated acids, in particular mineral acids,preferable examples of which include sulphuric acid or hydrochloric acidor hydrobromic acid; and also Lewis acids, preferable examples of whichinclude aluminium trichloride, boron trichloride or boron tribromide.The process variant a2) is preferably carried out using sulphuric acid.

[0053] The reaction temperatures during the operation of the processvariant a1) of the invention can be varied within a relatively widerange. In general, operation is effected at temperatures of from 100 to250° C., preferably at temperatures of 160 to 230° C., more preferablyat temperatures of 180 to 220° C.

[0054] The reaction temperatures during the operation of the processvariant a2) of the invention can be varied within a relatively widerange. In general, operation is effected at temperatures of from 100 to250° C., preferably at temperatures of from 120 to 230° C., morepreferably at temperatures of from 140 to 200° C.

[0055] The process variants a1) and a2) of the invention are generallyoperated under atmospheric pressure. However, it is also possible towork under pressure, in general from 1 bar to 10 bar.

[0056] To operate the process variant a1) of the invention for preparingthe compounds of the formula (I), generally from 2 to 10 mol, preferablyfrom 2 to 4 mol of base are used per mole of the compounds of theformula (II).

[0057] To carry out the process variant a2) of the invention forpreparing the compounds of the formula (I), generally from 1 to 10 mol,preferably from 1 to 3 mol of base are used per mole of the compounds ofthe formula (II).

[0058] The operation of the process variant a1) of the invention isgenerally effected as follows: the alkyldichlorobenzene derivatives ofthe general formula (II) are heated with a base in the presence of adiluent, and the water released by the reaction is continuouslydistilled off. The work-up is carried out by acidifying the reactionmixture with an acid and working it up by customary methods.

[0059] The operation of the process variant a2) of the invention isgenerally effected as follows: the alkyldichlorobenzene derivatives ofthe general formula (II) are heated with a base in the presence of adiluent, and the water released by the reaction is continuouslydistilled off, and the reaction mixture is worked up by customarymethods. The compounds of the formula (IV) obtained are treated withacid, and the reaction mixture is worked up by customary methods.

[0060] Useful diluents for operating the process variants b1) and b2) ofthe invention include primary alcohols, such as methanol, ethanol,n-propanol or i-propanol, or mixtures thereof with water. The processvariants b1) and b2) are preferably carried out using methanol.

[0061] The process variants b1) and b2) of the invention are operated inthe presence of a suitable acid acceptor. Useful acid acceptors includeall customary inorganic and organic bases. Preferable examples includealkaline earth metal or alkali metal hydroxides, alkoxides orcarbonates, such as sodium methoxide, potassium tert-butoxide, sodiumhydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.The process variants b1) and b2) are preferably carried out using sodiumhydroxide or, in particular potassium hydroxide.

[0062] To operate the process variant b1) of the invention, diluteacids, in particular mineral acids, are used, preferred examples ofwhich include sulphuric acid, phosphoric acid, and in particularhydrochloric acid.

[0063] To operate the process variant b2) of the invention, more highlyconcentrated acids, in particular mineral acids, are used, preferableexamples of which include sulphuric acid or hydrochloric acid orhydrobromic acid; and also Lewis acids, preferable examples of whichinclude aluminium trichloride, boron trichloride and boron tribromide.The process variant a2) is preferably carried out using sulphuric acid.

[0064] The reaction temperatures during the operation of the processvariant b1) of the invention can be varied within a relatively widerange. In general, operation is effected at temperatures of from 170 to250° C., preferably at temperatures of from 180 to 220° C.

[0065] The reaction temperatures during the operation of the processvariants b2) of the invention can be varied within a relatively widerange. In general, operation is effected at temperatures of from 100 to220° C., preferably at temperatures of from 150 to 200° C.

[0066] The process variants b1) and b2) of the invention are generallyoperated under elevated pressure. In general, operation is effected atpressures of from 1 to 130 bar, in particular at pressures of from 10 to40 bar.

[0067] To operate the process variant b1) of the invention for preparingthe compounds of the formula (I), generally from 2 to 10 mol, preferablyfrom 2 to 4 mol of base, are used per mole of the compounds of theformula (II).

[0068] To operate the process variant b2) of the invention for preparingthe compounds of the formula (I), generally from 1 to 10 mol, preferablyfrom 1 to 3 mol of base, are used per mole of the compounds of theformula (II).

[0069] Operation of the process variant b1) of the invention isgenerally effected as follows: the alkyldichlorobenzene derivatives ofthe general formula (II) are heated with a base in the presence of adiluent under pressure. After the end of the reaction, the reactionmixture is acidified with an acid and worked up by customary methods.

[0070] Operation of the process variant b2) of the invention isgenerally carried out as follows: the alkyldichlorobenzene derivativesof the general formula (II) are heated with a base in the presence of adiluent under pressure. The compounds of the formula (IV) obtained aretreated with acid, and the reaction mixture is worked up by customarymethods.

[0071] The process variant a1) of the invention is particularlypreferred.

[0072] The process of the invention is used in particular for preparing3-chloro-2-methylphenol, which is an important intermediate forpreparing pesticides (cf. WO 98/21189). By the process of the invention,3-chloro-2-methylphenol is obtained in constantly high purities and goodyields. The novel process therefore makes the preparation of knownpesticides easier.

[0073] The following examples serve to illustrate the invention.However, the invention is not limited to the examples.

EXAMPLE Example 1

[0074] 3-Chloro-2-methylphenol

[0075] Process Variant a1

[0076] 16.1 g (0.1 mol) of 2,6-dichlorotoluene and 19.8 g (0.3 mol) ofpotassium hydroxide (85%) are heated in 30 ml of diethylene glycol at abath temperature of 190° C. for 18 hours. The water released by thereaction is distilled off. After cooling, the reaction mixture isstirred with 100 ml of water until a solution is obtained and extractedthree times with 50 ml of dichloromethane. The aqueous phase is admixedwith 35 ml of 30% hydrochloric acid and extracted three times with 70 mlof dichloromethane. The organic phases are dried over sodium sulphateand concentrated under reduced pressure. 3-Chloro-2-methylphenol isobtained as a solid (12.4 g, content by HPLC: 83%, 72% of theory).

[0077] NMR (d⁶-DMSO): 6.75 (d, 1H, aromatic), 6.85 (d, 1H, aromatic) 7.0(t, 1H, aromatic), 9.8 (s, 1H, phenolic OH)

Example 2

[0078] 3-Chloro-2-methylphenol

[0079] Process Variant a1

[0080] 16.1 g (0.1 mol) of 2,6-dichlorotoluene, 19.8 g (0.3 mol) ofpotassium hydroxide (85%) and 0.3 g of dibenzo-18-crown-6 are heated in30 ml of diethylene glycol at a bath temperature of 190° C. with refluxfor 16 hours. The water released during the reaction is distilled off.After cooling, the reaction mixture is stirred with 100 ml of wateruntil a solution is obtained and extracted three times with 50 ml ofdichloromethane. The aqueous phase is admixed with 35 ml of 30%hydrochloric acid and extracted three times with 70 ml ofdichloromethane. The organic phases are dried and concentrated underreduced pressure. 3-Chloro-2-methylphenol is obtained as a solid (11.5g, content by HPLC: 97%, 78% of theory).

Example 3

[0081] 3-Chloro-2-methylphenol

[0082] Process Variant b1

[0083] 8.1 g (0.05 mol) of 2,6-dichlorotoluene and 9.9 g (0.15 mol) ofpotassium hydroxide (85%) are heated in 40 ml of methanol in anautoclave at 200° C. for 20 hours, which results in a pressure of 30bar. After cooling, the reaction mixture is poured into 250 ml of waterand extracted three times with 70 ml of dichloromethane. The aqueousphase is acidified to pH 1-2 with 30% hydrochloric acid and againextracted three times with 70 ml of dichloromethane each time. Theunited organic phases are dried over sodium sulphate and evaporatedunder reduced pressure to give a solid. 3-Chloro-2-methylphenol isobtained as a solid (6.2 g, content by HPLC: 93.5%, 82% of theory).

Example 4

[0084] 3-Chloro-2-methylanisole

[0085] Process Variant b2)—First Step—Preparation of Compounds of theFormula (IVa-1)

[0086] 8.1 g (0.05 mol) of 2,6-dichlorotoluene and 9.9 g (0.15 mol) ofpotassium hydroxide (85%) are heated in 40 ml of methanol in anautoclave at 160° C. for 20 hours, and the pressure rises to about 12bar. After cooling, the reaction mixture is poured into about 250 ml ofwater and extracted three times with about 70 ml of dichloromethane. Theunited organic phases are dried over sodium sulphate and evaporatedunder reduced pressure. 3-Chloro-2-methylanisole is obtained as an oil(2.5 g, GC analysis: 37.1%, 12% of theory).

[0087] Ret. index GC: 1187, m/e: 156

[0088] NMR (d⁶-DMSO) ppm: 2.2 (s, 3H, CH₃), 3.8 (s, 3H, O—CH₃), 6.95 (d,1H, aromatic),

[0089] 7.0 (d, 1H, aromatic), 7.2 (t, 1H, aromatic)

[0090] 3-Chloro-2-methylphenol

[0091] Process Variant b2)—Second Step—Preparation of Compounds of theFormula (I-1)

[0092] 3.1 g (0.02 mol) of 3-chloro-2-methylanisole are heated in 20 mlof 50% sulphuric acid for 18 hours with reflux. After cooling, thereaction mixture is extracted three times with dichloromethane, driedover sodium sulphate and concentrated to dryness under reduced pressure.3-Chloro-2-methylphenol is obtained as a solid (2.9 g, content by HPLC:11.7%, 12% of theory).

Example 5

[0093] 2-Chloro-6-[2-(2-hydroxyethoxy)-ethoxy]toluene

[0094] Process Variant b2)—First Step—Preparation of Compounds of theFormula (IVa-2)

[0095] 4 g (0.025 mol) of 2,6-dichlorotoluene and 2.4 g (0.036 mol) ofpotassium hydroxide (85%) are heated in 10 ml of diethylene glycol forfour hours under reflux. After cooling, the reaction mixture is stirredvigorously with water and extracted three times with dichloromethane.The organic phases are dried over sodium sulphate and are concentratedunder reduced pressure. 2-Chloro-6-[2-(2-hxdroxyethoxy)-ethoxy]tolueneis obtained as an oil (2.7 g, GC analysis: 32.3%, 15% of theory).

[0096] Ret. index GC: 1776, m/e: 230

[0097] NMR (d⁶-DMSO) ppm: 2.2 (s, 3H, CH₃), 3.5 (m, 4H, CH₂), 3.8 (m,2H, CH₂), (4.1 m, 2H, CH₂), 4.6 (m, 1H, OH), 6.9-7.2 (m, 3H, aromatic H)

1. Process for preparing compounds of the formula (I)

where R is C₁-C₆-alkyl, characterized in that compounds of the generalformula (II)

where R has the above meanings, are reacted a1) with a base in ahigh-boiling organic diluent of the general formula (III) R¹—OH   (III),where R¹is R²—O—(CH₂)₂—O—(CH₂)₂—, R²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—,R²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—O—(CH₂)₂— or —C₆ to C₁₀-alkyl, where R² ishydrogen, methyl or ethyl, optionally in the presence of a catalyst, andthe water released by the reaction is continuously removed, or arereacted a2) with a base in a high-boiling organic diluent of the generalformula (III) R¹—OH   (III), where R¹ has the above meanings, optionallyin the presence of a catalyst, and any water released during thereaction is continuously removed, and the resulting compounds of theformula (IV)

where R and R¹ have the above meanings, are treated with relativelyhighly concentrated acid, or are reacted b1) with a base in a primaryalcohol having 1 to 3 carbon atoms used as a diluent under pressure, orare reacted b2) with a base in a primary alcohol having 1 to 3 carbonatoms used as a diluent under pressure, and the resulting compounds ofthe formula (IV)

where R and R¹ have the above meanings, are treated with relativelyhighly concentrated acid.
 2. Process according to claim 1, characterizedin that the diluent used in the process variants a1) and a2) isdiethylene glycol.
 3. Process according to claim 1, characterized inthat the diluent used in the process variants b1) and b2) is methanol.4. Process according to claims 1 or 2, characterized in that the processvariants a1) and a2) are operated at temperatures of from 100° C. to250° C.
 5. Process according to any of claims 1 to 3, characterized inthat the process variant b1) is operated at temperatures of from 170° C.to 250° C.
 6. Process according to any of claims 1 to 3, characterizedin that the process variant b2) is operated at temperatures of from 100°C. to 220° C.
 7. Process according to claim 1, 2 or 4, characterized inthat the process variant a1) is operated as a one-pot process. 8.Compounds of the formula (IVa)

where R¹ is R²—(CH₂)₂—O—(CH₂)₂—, R²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—, orR²—O—(CH₂)₂—O(—CH₂)₂—O—(CH₂)₂—O—(CH₂)₂—, where R² is hydrogen, methyl orethyl.
 9. Compound of the formula (IVa-2)


10. Process according to any of claims 1 to 7, characterized in that thebase used is potassium hydroxide.